The range and variation in serum estradiol concentration in perimenopausal and postmenopausal women treated with transdermal estradiol in a real-world setting: a cross-sectional study

Abstract

Objectives: The aims of the study are to explore the range and variation in serum estradiol concentration, and to estimate the prevalence of "poor absorption" (women using licensed estradiol doses with subtherapeutic levels), in perimenopausal and postmenopausal women using transdermal estradiol in the real world.

Methods: This is a cross-sectional analysis in a specialist menopause clinic in the UK.

Results: Serum samples were obtained from 1,508 perimenopausal and postmenopausal women. A total of 61.87% were using licensed doses. The median estradiol concentration was 355.26 pmol/L (interquartile range 198.44-646.15 pmol/L). A reference interval for the whole cohort was defined as 54.62-2,050.55 pmol/L. There was substantial interindividual variation across the dose range. Variance was greater in younger women ( P = 0.002) and gel users ( P = 0.002). There was a trend toward greater variance in women using higher doses, but the association failed to reach statistical significance ( P = 0.074). One in four women (24.84%) using the highest licensed dose had subtherapeutic levels (<200 pmol/L). Older women (≥50 y) and patch users were more likely to have low levels (odds ratio 1.77, 95% confidence interval 1.22-2.62, P = 0.003; and odds ratio 1.51, 95% confidence interval 1.18-1.95, P = 0.001, respectively).

Conclusions: The reference interval for perimenopausal and postmenopausal women using on-label and off-label doses of transdermal estradiol in the real world is wide, and there is considerable interindividual variation. The number of estradiol users with low estradiol levels (<200 pmol/L) is higher than previously recognized. Measurement of serum estradiol can be helpful to identify women who may benefit from an off-label dose. Dose customization is key to ensure that all women can reap the benefits of HT.

FIG. 1

Relationship between log transformed serum estradiol concentration and estradiol dose for the whole cohort (N = 1,508). Dose was treated as a categorical variable to allow for nonlinearity, and because it was not possible to extrapolate beyond the licensed dose range. For example, one pump equivalent (PE) equates to one pump of 0.06% gel daily, or a 25-mcg patch twice weekly. Red diamonds represent the mean serum estradiol concentration per dose category. Blue, yellow, gray, and red dots represent levels within one, two, three, and four standard deviations from the mean, respectively. The log transformed model approximates a normal distribution with 69.4% of residuals within one SD of the mean, 95.5% within 2 SD, and 99.6% within 3 SD of the mean. The data points have been jittered for ease of visualization.

FIG. 2

Predicted estradiol concentration (95% confidence interval) according to estradiol dose, age and formulation using a linear model. The predicted values (plus 95% confidence intervals) of estradiol concentration (pmol/L) according to estradiol dose (number of pump equivalents, PE), age (<50 or ≥50 y) and estradiol formulation (patch or gel) from the linear model of log-transformed estradiol concentration. Gel users are shown in the left-hand plot, patch users are represented in the right-hand plot. Predicted values for women ≥50 years are shown in blue (n = 1,266, 83.95%); predicted values in younger women (<50 y) are shown in red (n = 242, 16.05%). The larger confidence intervals in women <50 years reflect a greater degree of uncertainty due to the smaller sample size. The plots demonstrate that at any given dose, predicted estradiol levels are greatest for women ≥50 years using estradiol gel. Whilst the predicted values increase with dose, the confidence intervals associated with off-label doses are larger and overlap, indicating a greater degree of uncertainty in the off-label dose range. One and seven PE were excluded from the model as there were insufficient data points (29 and 33 women respectively). > 8 PE was excluded from the model due to being a heterogeneous group.

FIG. 3

The percentage of women with low estradiol levels (<200 pmol/L) in each dose category. Dose (number of pump equivalents, PE) was treated as a categorical variable. The number of women with low or subtherapeutic levels (<200 pmol/L) decreases as the dose increases, but up to 1 in four women using the maximum licensed dose (4 PE) have low levels, and around 1 in 6 women using high off-label doses (5–8 PE) have low levels.